Spray compositions for inhalation therapy of bronchial disorders

ABSTRACT

Spray compositions, preferably in aerosol form, for inhalation therapy of bronchial disorders, especially acute or chronic asthma and acute or chronic obstructive bronchitis, containing as an active ingredient N-ethyl-norscopolamine methobromide or N-methyl-scopolammonium bromide optionally in combination with a mucolytic.

This is a continuation-in-part of copending application Ser. No. 487,054filed July 10, 1974 now abandoned; which is a continuation-in-part ofapplication Ser. No. 272,558 filed July 13, 1972, now abandoned.

This invention relates to novel pharmaceutical spray compositions forinhalation therapy of bronchial disorders, especially acute or chronicasthma and acute or chronic obstructive bronchitis, containing as anactive ingredient N-ethyl-norscopolamine methobromide orN-methylscopolammonium bromide, optionally in combination with amucolytic.

BACKGROUND OF THE INVENTION

Bronchial disorders, especially acute and chronic asthma, are presentlytreated primarily with bronchodilating catecholamine derivatives, suchas isoproterenol or metaproterenol, by means of various highly effectivepharmaceutical compositions, such as inhalation sprays, intravenous orintramuscular hypodermic solutions, or orally administerable powders ortablets. These catecholamine derivatives, however, most often producesignificant side effects which are typical for this class of compounds,such as tachycardia, cardiac arrhythmia and alterations of bloodpressure which may give rise to complications.

It is also known to treat bronchial disorders by intravenousadministration of a spasmolytic, but this method is also accompanied byundesirable side effects which are characteristic of spasmolytics,especially mydriasis and dryness of the mouth and tachycardia.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide effectivepharmaceutical inhalation spray compositions for the treatment ofbronchial disorders, such as asthma and chronic bronchitis, which arecompletely free from undesirable side effects.

It is another object of the instant invention to provide an effectivemethod for inhalation therapy of bronchial disorders, such as asthma,which does not produce the undesirable side effects often connected withthe presently employed treatment methods.

Still other objects and advantages of the invention will become apparentas the description thereof proceeds.

THE INVENTION

We have discovered that the above objects are achieved by means of spraycompositions, preferably in aerosol form, comprising as an activeingredient N-ethyl-norscopolamine methobromide or N-methylscopolammonium bromide, optionally in combination with a mucolytic.N-Ethyl-norscopolamine methobromide is particularly preferred as theactive ingredient.

The scopolamine derivatives employed in accordance with the presentinvention are known compounds. Thus,

A. N-ethyl-norscopolamine methobromide is disclosed in GermanOffenlegungsschrift 1,670,048 and U.S. Pat. No. 3,472,861; and

B. N-methyl-scopolammonium bromide is disclosed in U.S. Pat. No.2,753,288.

The inhalation spray compositions pursuant to the present invention areprepared in conventional manner by dissolving or suspending the activeingredient in a suitable liquid substrate, and filling the resultingsolution or suspension into a suitable container from which it can beexpelled as an atomized spray or an aerosol through a suitable nozzle orvalve. The active ingredient concentration in the solution or suspensionshould be 0.007 to 1.0% by weight, based on the total weight.

The single effective therapeutic dosage range of N-ethyl-norscopolaminemethobromide or N-methyl-scopolammonium bromide for inhalation spraytherapy is from 5 to 100 γ. Normally, a dose of 5 to 50 γ is sufficientto relieve bronchial spasms due to acute or chronic asthma or chronicbronchitis while somewhat higher dosages up to 100 γ are required torelieve bronchial spasms due to acute bronchitis. consequently, thedesign of the container should be such that each actuation of the meansfor expelling the solution or suspension therefrom ejects a measuredamount of spray or aerosol containing the desired amount of activeingredient.

The container may be a simple squeeze bottle or piston- or bulb-operatedatomizer provided with a suitable atomizing nozzle, or preferably anaerosol spray can provided with a metering aerosol valve.

The inhalation spray compositions according to the present invention mayalso contain an effective amount of a mucolytic, such asN-cyclohexyl-N-methyl-(2-amino-3,5-dibromo-benzyl)-ammonium chloride orN-acetyl-L(+)-cysteine.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below. The percentages are percent by weight.

EXAMPLE 1 Aerosol

The aerosol composition is compounded from the following ingredients:

    ______________________________________                                        N-ethyl-norscopolamine methobromide                                                                  0.007 - 0.7%                                           Sorbitan trioleate (surfactant)                                                                      0.5 - 2%                                               Mixture of monofluoro-trichloro-                                               methane and difluoro-dichloro-                                                methane (40 : 60)     q.s.ad 100%                                            ______________________________________                                    

Preparation

The ingredients are admixed with each other in conventional fashion, andthe mixture is filled into aerosol spray cans provided with a meteringvalve which meters out with each actuation an amount of aerosolcontaining from 5 to 100 γ of the norscopolamine compound. The aerosolexpelled from the spray can is an inhalation spray composition witheffective bronchospasmolytic action.

EXAMPLE 2 Inhalation spray with mucolytic

The spray composition is compounded from the following ingredients:

    ______________________________________                                        N-methyl scopolammonium bromide                                                                      0.007 - 0.5%                                           Solution of N-cyclohexyl-N-methyl-                                             (2-amino-3,5-dibromo-benzyl)-                                                 ammonium chloride in distilled                                                water (2 mgm/ml)      q.s.ad 100%                                            ______________________________________                                    

Preparation

The scopolammonium compound is dispersed in the aqueous solution, andthe mixture is filled into squeeze bottles provided with an atomizingvalve which expels with each squeeze an amount of mist containing 5 to100 γ of the scopolammonium compound. The mist expelled from the squeezebottle is an inhalation spray composition with effectivebronchospasmolytic and mucolytic action.

The same results are obtained when the aqueous solution of the mucolyticis replaced by an equal amount of an aqueous solution (0.2 gm/ml) ofN-acetyl-L(+)-cysteine or cysteine-N-acetic acid hydrochloride.

EXAMPLE 3 Inhalation spray

The spray composition is compounded from the following ingredients:

    ______________________________________                                        N-ethyl-norscopolamine methobromide                                                                  0.005 - 0.4%                                           Phosphate buffer solution (pH 5)                                                                     q.s.ad 100%                                            ______________________________________                                    

Preparation

The norscopolamine compound is dissolved in the buffer solution, and theresulting solution is filled into bottles provided with apiston-operated atomizer nozzle which expels with each actation of thepiston an amount of mist containing 5 to 100 γ of the norscopolaminecompound. The mist is an inhalation spray composition with effectivebronchospasmolytic action.

The amounts and nature of the inert liquid carrier ingredient in theseillustrative examples may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. An inhalation spray composition for treating bronchialdisorders, consisting essentially of a pharmaceutically inert liquidcarrier and 0.007 to 1% by weight, based on the total weight, ofN-ethyl-norscopolamine methobromide or N-methyl-scopolammonium bromide.2. An inhalation spray composition of claim 1, wherein saidpharmaceutically inert liquid carrier is a mixture of a major amount ofa physiologically acceptable liquified aerosol propellant gas and aminor amount of a surfactant.
 3. An inhalation spray composition ofclaim 1, additionally comprising an effective amount of a mucolyticagent.
 4. The method of relieving bronchial spasms in human patients,which comprises administering to said patients by the respiratory routefrom 5 to 100 γ of N-ethylnorscopolamine methobromide orN-methyl-scopolammonium bromide.